Monoclonal gammopathy of undetermined significance (MGUS) occurs in 4% of the population over 50 years old and represents a precursor lesion to myeloma. Although several studies have examined the immune response to antigens in human cancer including myeloma, the nature of immune response against preneoplastic lesions is less studied. This application builds on our recent findings that a large proportion of patients with MGUS harbor spontaneous immune responses against antigens expressed on embryonal / cancer stem cells. In preliminary studies, the detection of these responses predicted reduced probability of disease progression. The specific objectives of the studies in this application are 1) to better understand this naturally occurring immune response in MGUS; 2) to further evaluate the basis of the absence of these responses in myeloma patients; and 3) to understand the clinical and prognostic significance of immunity to stem cell antigens in these patients in the context of a prospective clinical trial. These studies have direct implications for approaches to boost host immunity against myeloma stem cells and harnessing properties of host response for risk assessment and early detection of cancer.